The present invention relates to the field of asymmetric hydrogenation and, more particularly, to the use of novel Ru(II) chiral catalysts for the asymmetric hydrogenation of substrates which, as a result of their weak donor capability and of their hindered structures, have proved heretofore very difficult or impossible to hydrogenate.
A great number of chiral metal catalysts has been used in the past to asymmetrically hydrogenate a variety of substrates.
In the context of the present invention, we can cite in particular the efforts of two research groups which actively studied the synthesis of Ru(II) chiral catalysts, obtained from the Ru(II) complex of formula [(COD)Ru(2-methylallyl)2] (COD=cyclo-1,5-octadiene).
Thus, J.-P. Genet and his collaborators have published work related to catalysts of formula [Ru(P*-P*)(2-methylallyl)2], wherein P*-P* represents a diphosphine ligand of the type of those currently known under abbreviated designations such as DIOP, CHIRAPHOS, PROPHOS, BDPP, CBD, NORPHOS, DEGUPHOS, BPPM, BINAP, R-DuPHOS (R=methyl or ethyl), BIPHEMP or yet DIPAMP (see, for example, J.-P. Genet et al., Tetrahedron : Asymmetry 1991, 2, 43). Such catalysts were obtained by heating the above-mentioned Ru(II) complex together with the appropriate chelating diphosphine, in a solvent such as hexane or toluene, such as to replace the cyclooctadiene with the chiral phosphine.
Upon subsequent work (see, for example, WO 91/02588; J.-P. Genet, Acros Organics Acta, 1994, 1, 1-8; J.-P. Genet et al., Tetrahedron: Asymmetry, 1994, 5, 665-690), these authors described the transformation of such catalysts via protonation by means of aqueous acids such as HBr, HCl, HF or HBF4, in strongly coordinating solvents, capable of playing a role in stabilizing the coordination structure around the metal, which structure, according to the same authors, is of the hexacoordinate type. This kind of catalysts, which can be prepared in situ, proved to be useful for the asymmetric hydrogenation, in protic or strongly electron-donating solvents (methanol, ethanol or their mixtures with other solvents), of substrates comprising carbonyl groups and acyclic ethylenic bonds.
Other studies (see, for example, F. Heiser et al., Tetrahedron: Asymmetry, 1991 2, 51-62; EP 643 052; EP 398 132; EP 570 674) have resulted in reports of the use of catalysts prepared in situ for hydrogenating a variety of substrates, starting from the same ruthenium complex, but following a process according to which a mixture of said complex and an appropriate diphosphine ligand is treated with namely CF3COOH, once again in an electron-donor solvent able to stabilize the coordinating structure of the metal.
These catalysts, and others obtained according to similar processes described in the cited references, reveal themselves very efficient in the asymmetric hydrogenation of various substrates, often good electron-donor substrates capable of coordinating the Ru(II), and are typically used with protic solvents, or mixtures of protic and aprotic solvents. However, they proved to be inefficient when used, under the prior art conditions, for the hydrogenation of substrates possessing heavily hindered ethylenic bonds, for example tetrasubstituted double bonds, in particular when the latter are part of ring systems.
In published International patent application No. WO 97/18894, filed on Nov. 20, 1996, we describe new Ru(II) catalysts and teach their successful use for asymmetrically hydrogenating this type of particularly hindered substrates. More particularly, there is described the hydrogenation of cyclopentenone derivatives of formula(II). 
wherein R1 represents a linear or branched C1 to C4 alkyl radical and R2 represents a saturated or unsaturated, linear or branched, C1 to C8 hydrocarbon radical, the hydrogenation of which had proved impossible until our discovery of novel catalysts obtained by an original process.
The catalysts described in the above-mentioned patent application were obtained by a method which comprised treating equimolar amounts of an appropriate Ru(II) complex, for example, [(COD)Ru(2-methylallyl)2] and a chelating diphosphine with an acid of formula HX, wherein X is a non-coordinating anion, said acid being used in a ratio not exceeding 2 molar equivalents per mole of the Ru(II) complex and the treatment being carried out in a non-coordinating or weakly coordinating medium, under an inert atmosphere.
Such catalysts were able to successfully hydrogenate substrates (formula II), amongst others, to provide their corresponding saturated homologues in strictly cis-configuration and with an enantiomeric excess of at least 60% in the (+)-1R-isomer. Such catalysts, and their use in asymmetric hydrogenation reactions, provided a breakthrough of outstanding importance for the single-step conversion of unsaturated substrates which had previously proved impossible to hydrogenate, into their saturated homologues. Moreover, their use in the conversion of substrates (formula II)-proved particularly valuable in the case of methyl 3-oxo-2-pentyl-1-cyclopentene-1-acetate, the asymmetric hydrogenation of which provided, in a single step, the preferred optically active isomer of methyl dihydrojasmonate or Hedione(copyright) (origin: Firmenich SA, Geneva, Switzerland), a well-known and widely used perfume ingredient.
In fact, amongst the four possible Hedione(copyright) stereoisomers, methyl (+)-(1R)-cis-3-oxo-2-pentyl-1-cyclopentaneacetate is known to develop at their best the odor characters, and namely the jasmine note, for which Hedione(copyright) is notorious, while the strength of this isomer""s odor is also superior to that of the other isomers by several orders of magnitude. Therefore, the production of methyl (+)-(IR)-cis-3-oxo-2-pentyl-1-cyclopentaneacetate in an optically pure state, or of isomer mixtures which contain essentially this isomer, is of capital importance in the fragrance industry.
One object of the present invention is a ruthenium catalyst obtainable by a process which comprises putting into contact an appropriate Ru(II) complex, a chelating diphosphine and an acid comprising a non-coordinating anion, said Ru(II) complex and chelating diphosphine being present in equimolar amounts, the contact occurring in a non-coordinating or weakly coordinating medium and under an oxygen-free atmosphere, wherein the acid comprising the non-coordinating anion is used in an amount of about I molar equivalent per mole of the Ru(II) complex.
Reference to xe2x80x9cabout 1 molar equivalent of acid per mole of Ru(II) complexxe2x80x9d signifies here a molar ratio between these two components which does not significantly differ from 1, and is preferably comprised within a range of between 0.95 and 1.10, more preferably from 1.0 to 1.10.
The above-mentioned catalysts of the invention provide surprisingly good results when used in the hydrogenation of substrates (II) in particular, but can also be conveniently used for the hydrogenation of substrates of general formula III 
as defined in claim 12. Preferred embodiments of the hydrogenation process of the invention relate to the hydrogenation of substrates (formula III) having a carbon-carbon double bond in one of the positions indicated by the dotted lines which is at least trisubstituted, i.e. not more than one amongst the R2, R3 and R4 groups represents hydrogen.
It will be apparent to the person skilled in the art from the disclosure which follows that the catalysts of the invention can also be successfully used in the hydrogenation of ethylenic bonds less sterically hindered than those of preferred substrates (formula III) described above. However, they are most advantageously used in the one-step conversion of the preferred substrates (formula III) defined above into their saturated homologues, as is apparent hereafter, particularly those wherein the double bond is tetrasubstituted.
We have in fact ascertained that the catalysts of the invention can be successfully and generally used in asymmetric hydrogenations and are able to readily hydrogenate di-, tri- and tetrasubstituted double bonds, isolated or occured in xcex1,xcex2- or xcex2,xcex3-position to an ester function, in xcex1,xcex2-position to a ketone or aldehyde function and even in xcex2,xcex3-position to an alcohol function, the ester and ketone groups being totally unaffected by the hydrogenation.
The catalysts of the invention comprise, or consist essentially of, the reaction product of the appropriate Ru(II) complex, the chelating diphosphine and the acid comprising the non-coordinating anion, the reaction occurring in a non-coordinating or weakly coordinating medium.
By an xe2x80x9cappropriate Ru(II) complexxe2x80x9d it is meant here any of the Ru(II) complexes currently known and used in the preparation of ruthenium catalysts, amongst which can be cited for example those wherein the metal is surrounded by dienyl and alkyl type ligands, such that the metal is "sgr"-bonded to two of said ligands, which ligands further possess at least one bond xcfx80-bonded to the metal, two other coordination positions being xcfx80-bonded to the same said two ligands or to a distinct ligand.
Several ruthenium compounds are known from the prior art which comprise ligands fulfilling the above-mentioned conditions and which are convenient as precursors of the catalysts of the present invention.
One can cite more particularly, as appropriate ruthenium(II) complexes, the compounds of the [(diene)Ru(allyl)2] type, wherein xe2x80x9cdienexe2x80x9d stands for example for COD (cycloocta-1,5-diene) or NBD (norbornadiene), or yet hepta-1,4-diene, and xe2x80x9callylxe2x80x9d represents an allyl or 2-methylallyl radical (see, for instance, J.-P. Genet et al., cited references; M. O. Albers et al., Inorganic Synth., 1989, 26, 249; R. R. Schrock et al., J. Chem. Soc. Dalton Trans., 1974, 951). Other appropriate ruthenium(II) complexes include the compounds of the [bis(pentadienyl)Ru] type, wherein xe2x80x9cpentadienylxe2x80x9d stands for a pentadienyl, 2,4-dimethylpentadienyl, 2,3,4-trimethylpentadienyl, 2,4-di(tert-butyl)-pentadienyl or yet 2,4-dimethyl-1-oxapentadienyl radical (see, for example, R. D. Ernst et al., J. Organometallic Chem., 1991, 402, 17; L. Stahl et al., Organometallic 1983, 2, 1229; T. Schmidt et al., J. Chem. Soc. Chem. Commun., 1991, 1427; T. D. Newbound et al., Organometallics, 1990, 9, 2962).
Yet other appropriate Ru(II) complexes include [Ru(COD)(COT)], wherein COT stands for cycloocta-1,3,5-triene, [bis(2,4-cyclooctadienyl)Ru] and [bis(2,4-cycloheptadienyl)Ru] (see, for example, P. Pertici et al., J. Chem. Soc. Dalton Trans., 1980, 1961; Inorganic Synthesis 1983, 22, 176) and [Ru(NBD)(CHT)] wherein NBD is norbornadiene and CHT stands for cyclohepta-1,3,5-triene (see for example, H. Nagashima et al., J. Organometallic Chem. 1983, 258, C15).
Following a preferred embodiment of the catalysts of the invention, there is used as the Ru(II) precursor, the compound of formula: [(COD)Ru(2-methylallyl)2], bis(2,4-dimethylpentadienyl)ruthenium (e.g. L. Stahl et al. or T. D. Newbound et al., references cited), bis(2,4-dimethyl-1-oxapentadienyl) ruthenium complexes (e.g. T. Schmidt et al., reference cited) or yet [Ru(COD)(COT)] (P. Pertici et al., ref. cited). [(COD)Ru(2-methylallyl)2], the preparation of which was first reported by J. Powell et al., in J. Chem. Soc., (A), 1968, 159 (see also M. O. Albers et al., Inorganic Synthesis 1989, 26, 249, and [Ru(COD)(COT)] proved quite convenient from a practical point of view.
Amongst the chelating diphosphines which can be used as ligands in the catalysts of the invention, there can be cited as preferred embodiments those selected amongst the known chiral diphosphine or bis(phosphine) ligands which make it possible to obtain catalytic species convenient for homogeneous asymmetric hydrogenations. More particularly, such chiral diphosphines include those known under the abbreviations of Me-DuPHOS, Et-DuPHOS, BINAP, ToIBINAP, SKEWPHOS, DIPAMP and CHIRAPHOS, the structures of which are represented hereafter for one of the enantiomers in particular, and wherein Ph stands for a phenyl group: 
Other chiral bidentate phosphines which can be used in the chiral catalysts of the invention include for instance those known under the name of NORPHOS, or yet the analogues of the DuPHOS type ligands, so-called xe2x80x9cBPExe2x80x9d, the structures of which are represented hereafter for one of the enantiomers. 
All such ligands are either commercially available or can be prepared by methods previously reported in the literature.
Other particularly useful ligands for the preparation of the catalysts of the invention are the chiral diphosphines described for example in European patent applications nos. 564 406, 612 758 and 646 590, which disclose a large number of ligands appropriate for the catalysts according to the present invention. The contents of these documents, inasmuch as they relate to the definition and preparation or said chelating diphosphines, are hereby included by reference.
Amongst the chelating diphosphines described in EP 564 406, EP 612 758 and 646 590, it is preferred to use those obeying the general formula(Lxe2x80x28) 
wherein Z is a phosphorus atom and R and Rxe2x80x2 are, independently from each other, a C1 to C4 alkyl group, linear or branched, a cyclohexyl group, a phenyl group or a phenyl group substituted by 1 to 3 alkyl groups having 1 to 4 carbons, the latter alkyl groups possibly being partially or totally fluorinated.
Even more preferred ligands of this type are those of formula 
and, more particularly, that known under the designation of (R)-(S)-JOSIPHOS (R=cyclohexyl, Rxe2x80x2=phenyl) or (xe2x88x92)-JOSIPHOS, or yet its derivatives such as (R)-(S)-CF3-JOSIPHOS.
Moreover, we also observed that the catalysts of the invention proved advantageous for the hydrogenation of many substrates, in particular those of formula (II), with a cis-stereoselectivity close to 100%, when they comprised in their structure both chiral and achiral chelating diphosphines. Thus, useful achiral ligands include for example the achiral or racemic ferrocenyl diphosphines represented hereafter: 
Other bidentate phosphines useful as ligands are represented below: 
In the context of the invention, there can yet be cited the optically active diphosphines of formula (L14) 
as well as the corresponding racemic mixtures of isomers, reported in International patent application WO 96/20202. The contents of the latter related to the preparation of such ligands are hereby included by reference.
In a general manner, there can be used as ligands in the catalysts of the invention any chelating diphosphines comprising substituent groups capable of rendering the diphosphine sufficiently electron-rich to allow it to stabilize the metal, without however depriving said metal of its ability to coordinate the substrate to be hydrogenated and more particularly substrates of formula (II) and (III) mentioned above, the asymmetric hydrogenation of which had proved heretofore notoriously difficult, if not impossible.
It has also been observed that the diphosphines having a certain number of alkyl or cycloalkyl type substituents revealed themselves particularly useful for the aim of the invention and provided catalysts which were very active and efficient for the hydrogenation of substrates of formula (II) and (III).
It is apparent from the above that the preferred ligands for preparing the catalysts of the invention are diphosphine ligands in which the two phosphorous atoms are bridged by groups of the alkyl, 1,2-benzenyl, bis(naphthalenyl) or yet 1,1xe2x80x2-ferrocenyl type, optionally substituted, said phosphorous atoms further carrying two other substituents, which can be identical or different and formed of alkyl, aryl or alkylaryl radicals, or yet alicyclic radicals.
However, it is impossible to exhaustively illustrate here all the ligands which can be used in the catalysts of the invention and many other chelating diphosphines, not specifically cited above, or not falling under the above definitions, prove useful for the aim of the latter. The examples given illustrate preferred embodiments which are not to be interpreted as restricting the scope of the invention, inasmuch as the person skilled in the art is well able, without particular effort and using her general knowledge to select such ligands so as to achieve the aim described. To this effect, the skilled person can also find inspiration in the many prior art references, namely those cited in this description, to select many such ligands which, when used according to the invention here-described, make it possible to obtain catalysts able to achieve the same effect, i.e. hydrogenate substrates of formula (II) and (III) with essentially cis-stereo-selectivity (90% or more) for (formula II) and providing, where applicable, an excess of at least 60% in one of the cis-enantiomers.
The catalysts of the invention which comprise diphosphine ligands of the DuPHOS, BINAP, ToIBINAP, SKEWPHOS or JOSIPHOS type are particularly advantageous as catalysts for the asymmetric hydrogenation of the substrates of formula (If) and (III).
Amongst the latter catalysts, those which comprise ligands of the SKEWPHOS, JOSIPHOS or Me-DuPHOS type, and preferably of the two latter types, showed themselves capable of particularly advantageous performances and are therefore preferred according to the invention. (R,R)-(xe2x88x92)-Me-DuPHOS, or (xe2x88x92)-1,2-bis(2,5-dimethyl-phospholano)benzene, and (R)-(S)-JOSIPHOS or (R)-(S)-CF3-JOSIPHOS, made it possible to obtain choice catalysts according to the invention.
The ligands having formula L1 to L14 represented below are either commercially available compounds or they can be prepared according to processes analogous to previously described methods.
For example, the ligands of the DuPHOS, SKEWPHOS, BINAP, CHIRAPHOS, DIPAMP and NORPHOS type are mostly commercial products and, in any event, they can be obtained via processes described in the literature, namely in reference works such as the books of R Noyori, Asymmetric Catalysis in Organic Synthesis, John Wiley and Sons, N.Y. (1994), Chap. II and J. Ojima, Catalytic Asymmetric Synthesis, VCH Publishers, N.Y. (1994), Chap. 1, and the original references there-cited wherein such ligands were first reported.
The ligands of formula (L7) can be prepared as described for example in U.S. Pat. No. 5,171,892.
The ligands of formula (L8) and (Lxe2x80x28) can be prepared as described in the references already cited (see also A. Togni et al., J. Amer. Chem. Soc. 1994, 116, 4062) and some of them are commercially available (Rcyclohexyl, Rxe2x80x2=phenyl for example; origin: STREM Chemicals, Inc.).
The ferrocenyl ligands of formula (L9), (L10) or (L11), when not available commercially, can be prepared by methods analogous to those reported in the literature (see, for example, I.R. Butter et al., Synth. React. lnorg. Met.-Org. Chem., 1985, 15, 109; M.D. Rausch et al., J. Organometallic Chem., 1967, 10, 127; R.A. Brown et al., Polyhedron 1992, 20, 2611; G. Herberich et al., Chem. Ber., 1995, 128, 689) starting from ferrocene and according to the following reaction schemes: 
The (L12) and (L13) ligands are quite common and many are commercialized. Amongst the (L13) ligands, those wherein n=0 can be prepared by a variety of known methods (see, for example, R. Appel et al., Chem. Ber., 1975, 108, 1783 and references cited therein; M. Baudler et al., Chem. Ber. 1972, 105, 3844; K. Issleib et al., Journal fiir Praktischc Chemie, 1969, 311, 463).
The non-coordinating anion to be used in the catalysts of the invention can be a base conjugate of a variety of strong acids and includes for example the anions selected from the group consisting of BF4xe2x88x92, PF6xe2x88x92, SbF6xe2x88x92, AsF6xe2x88x92 and B[3,5-(CF3)2C6H4]4xe2x88x92. Thus, suitable acids that contain this conjugate anion include, amongst others, those of formula RBF4, RPF6, RSbF6, RAsF6, and RB[3,5-(CF3)2C6H4]4 wherein R represents hydrogen or a (C6H5)3C group.
According to a preferred embodiment of the invention, the non-coordinating anion is a base conjugate of an acid of formula H-Anion, wherein the anion is selected amongst the anions BF4xe2x88x92, PF6xe2x88x92, SbF6xe2x88x92, AsF6xe2x88x92, or yet HB[3,5-CF3)2C6H4]4xe2x88x92. Such acids are typically used in the form of the corresponding etherates (for example HBF4.R2O, R=CH3 or C2H5) or of any other onium type salt (phosphonium for example). These etherates are commercial products, or they can be prepared from the corresponding silver salts, by reacting with HCl. In the latter case, the silver salt, for example AgBF4, AgPF6, AgSbF6 or AgAsF6 will be typically reacted with HCl, in a solvent containing a dialkylether, for example a mixture of dicholormethane and diethylether. As the silver chloride precipitates, it provides the etherate solution of the acid, which can then be used according to the invention in the reaction with the ruthenium complex and the phosphine ligand.
Amongst the above-mentioned H-Anion acids, wherein the anion represents the non-coordinating anion, tetrafluoroboric acid is preferred and typically used in the form of its etherate, as commercially available in glass or plastic vials. If necessary, this product is titrated to ensure that the concentration of acid is about 1 molar equivalent of the molar amount of Ru complex.
The reaction according to which the catalyst of the invention can be obtained occurs in a non-coordinating or weakly coordinating medium and under an oxygen-free atmosphere. By an xe2x80x9coxygen-free atmospherexe2x80x9d it is meant here an atmosphere whose oxygen content is lower than 200 ppm, and preferably not above 5 to 10 ppm.
By the xe2x80x9cnon-coordinating or weakly coordinating mediumxe2x80x9d it is typically meant here a non-coordinating or weakly coordinating solvent. Examples of suitable solvents include esters, ketones, aliphatic, acyclic or cyclic hydrocarbons, chlorinated hydrocarbons and ethers, as long as they have no capability to strongly coordinate the ruthenium. Specific examples include dichloromethane, dichloroethane, ethyl pivalate, methyl acetate, ethyl acetate, isopropyl acetate, acetone, 2-butanone, 3-pentanone, hexane, heptane, cyclohexane, cycloheptane and methyl tert-butyl ether.
According to a preferred embodiment, dichloromethane or a mixture of it with other, non-coordinating or weakly coordinating solvents, in particular those mentioned above, is used.
It should be noted that the use of the strongly coordinating or protic solvents current in the art for the preparation of Ru catalysts, provided species which were inactive or inadequate for the hydrogenation of the substrates of formula (II) or (III) previously mentioned.
The non-coordinating or weakly coordinating medium may also consist of a mixture of a solvent such as described above with a substrate of formula (II) or (III), or even essentially ofjust said substrate of formula (II) or (III).
Thus, according to an embodiment of the invention there is provided a catalyst obtainable in the presence of an organic non-coordinating or weakly coordinating solvent and/or of a substrate of formula 
having a double bond in one of the positions indicated by the dotted lines and wherein
a) n=0 and Y represents hydrogen, a C1 to C4 linear or branched alkyl radical or an OR1 group, R1 standing for a linear or branched lower alkyl radical; or
b) n=1, X represents a CH2 group and Z stands for an OR1 group wherein R1 has the meaning cited in a); or
c) n=1, X represents an oxygen atom and Z represents a C1 to C4 linear or branched alkyl radical, or X represents a NR5 group, R5 standing for a lower alkyl radical, and Z stands for a linear or branched C1 to C4 alkyl radical;
and wherein
R2 represents hydrogen or a saturated or unsaturated, linear or branched C1 to C8 radical derived from a hydrocarbon;
R3 and R4 are taken separately and each represents hydrogen or a saturated or unsaturated, linear or branched C1 to C8 radical derived from a hydrocarbon, or are taken together to form a five-membered or six-membered ring which also contains the carbon atoms of the ethylenic bond.
Preferred substrates of the invention are compounds of formula (III) wherein not more than one of the R2, R3 and R4 symbols represents hydrogen.
By a lower alkyl radical it is meant here a C1 to C4, linear or branched alkyl radical.
When the catalyst of the invention is obtained in the presence of the 20 substrate, preferred embodiments of said catalyst include the presence of substrates formed of compounds of formula(II) 
wherein R1 is a linear or branched alkyl radical from C1 to C4 and R2 is a saturated or unsaturated, linear or branched, C1 to C8 hydrocarbon radical,
or of formula 
having a double bond in one of the positions indicated by the dotted lines and wherein:
a) n=0 and Z represents an OR1 group, R1 standing for a C1 to C4 linear or branched alkyl radical;
or
b) n=1, and Z represents a C1 to C4 linear or branched alkyl radical; and wherein R2 is a saturated or unsaturated, linear or branched, C1 to C8 hydrocarbon rest and R6, R7 and R8 represent each hydrogen or a lower alkyl radical of C1 to C4.
In this context, particularly useful catalysts are those wherein the substrate present in the reaction medium is a compound of formula (IV) in which n=0 and Y represents a OR1 group wherein R1 represents a methyl or ethyl group, R2 represents a methyl radical and R6, R7 and R8 are identical or different and represent each hydrogen or a methyl group.
More preferred substrates are methyl 3-oxo-2-pentyl-1-cyclopentene-1-acetate and methyl 2,6,6-trimethyl-2-cyclohexene-1-carboxylate, which, as will become apparent shortly, make it possible to obtain preferred isomers of useful perfume ingredients, amongst which Hedione(copyright).
As previously mentioned, the medium in which the reaction takes place can also be a mixture of one of the substrates mentioned above and a non-coordinating or weakly coordinating solvent, in which case the latter will be preferably chosen amongst the solvents already cited above, and more preferably as a solvent comprising dichloromethane.
The catalysts of the invention described above are extremely active species which have been found to improve upon those described in the WO 97/18894 patent application. In fact, although the catalysts described in the above document are quite appropriate for the hydrogenation of the same type of ethylenic bonds and substrates as are here contemplated, we have now unexpectedly discovered that complete conversion of these substrates can now be obtained, by means of the presently claimed catalysts, in even shorter reaction times, while using lower amounts of catalyst.
Amongst the catalysts of the invention described above, particularly effective species for the asynmnetric hydrogenation of methyl 3-oxo-2-pentyl-1-cyclopentene-1-acetate were those wherein the Ru(II) complex is [(COD)Ru(2 -methylallyl)2] and the anion BF4xe2x88x92 derived from HBF4.etherate, and wherein (R,R)-(xe2x88x92)-Me-DuPHOS or (R)-(S)-JOSIPHOS was used in a medium comprising dichloromethane, in both cases preferably in the presence of the substrate mentioned here-above.
The invention further realizes a process for the preparation of a ruthenium catalyst, characterized in that an appropriate Ru(II) complex and a chelating diphosphine present in equimolar amounts, and an acid comprising a non-coordinating anion, are reacted under an oxygen-free atmosphere and in a non-coordinating or weakly coordinating medium, wherein the acid comprising the non-coordinating anion is used in an amount of about 1 molar equivalent per mole of the Ru(II) complex.
The nature of the parameters of this process, i.e. the Ru(II) complex, the chelating diphosphine, the non-coordinating anion and the reaction medium, have been described in detail above.
According to the invention, the preparation of the catalyst can be carried out at room temperature or at a lower temperature. Higher temperatures may also be used, and can be chosen such as not to influence the catalyst""s properties and its efficiency in the hydrogenation of the substrates. Nevertheless, the application of room temperature proves to be advantageous from a practical point of view.
As mentioned before, the catalyst is prepared under inert, oxygen-free atmosphere, typically under argon or nitrogen.
Preferred embodiments of this process correspond to the use of the preferred parameters already described above with regard to the catalysts, e.g. the use of optically active diphosphines, preferred anions and so on.
In particular, the preparation of the catalyst in a medium consisting of a non-coordinating or weakly coordinating solvent and a small amount of substrate, in particular substrates of formula (II) or (IV), turns out to be a very advantageous embodiment of the process of the invention.
The catalysts according to the present invention which have been prepared like this are obtained as solutions, in the solvent and the substrate, of the product which is the result of the reaction of the Ru(II) complex with the diphosphine ligand and the acid from which the anion is derived. These catalytic solutions may be used as such for the asymmetric hydrogenation of the substrates, namely compounds of formula (II) and (IV). They can be kept under an oxygen-free atmosphere and will stay active for several days.
Catalytic solutions according to the present invention are thus obtained, having a variable concentration in the catalyst of the invention, for example of the order of 0.04 to 0.07 M (0.04 to 0.07 mmoles of catalyst/ml of catalytic solution), and more preferably of the order of 0.055 M, which proved to be very advantageous for the hydrogenation of substrates of formula (I) and (IV) in particular.
Preferred pre-catalysts of the invention are those of formula (V)
[Ru (P*xe2x80x94P*)(H)(triene)]+ Anionxe2x80x83xe2x80x83(V)
wherein P*xe2x80x94P* represents a chelating bis(phosphine)ligand, possibly chiral, X represents a non-coordinating anion and xe2x80x9ctrienexe2x80x9d stands for cyclohepta-1,3,5-triene, cycloocta-1,3,5-triene or a similar species. These most preferred compounds require the presence of at least one COD molecule in the precursor ruthenium (II) complex. According to a preferred embodiment of this catalyst, the diphosphine is (R,R)-(xe2x88x92)-Me-DuPHOS or (R)-(S)-JOSIPHOS and the anion is BF4xe2x88x92.
Other embodiments of this catalyst are apparent from the text above, the diphosphine ligand and the anion being varied at will, having the meaning previously defined and being specifically cited above with regard to particular examples of the catalysts of the invention.
The preparation of preferred embodiments of the catalysts of formula (V) are described in detail further on.
The ruthenium catalysts of the invention are useful for the hydrogenation, optionally asymmnetric, of carbon-carbon double bonds in general and more particularly highly sterically hindered ones.
Their activity with regard to the hydrogenation of the substrates of formula (II), (III) and (IV) in particular is excellent, unlike what is the case of the prior art ruthenium catalysts. They enable the preparation of the saturated compounds corresponding to substrates of formula (II) and (IV) with a cis-stereoselectivity above 95% and, in most cases of the order of 98% or more. When chiral chelating bis(phosphines) are present in the structure of the catalysts of the invention, the asymmetric hydrogenation of the above-mentioned substrates provides enantiomers with at least 60% e.e., and in many cases above 85% ee.
According to preferred embodiments of the invention, there are thus also provided processes for the preparation of compounds resulting from the hydrogenation of compounds of formula (II) and (IV).
Therefore, the invention also relates to a process for the preparation of a compound of formula 
wherein R1 is a linear of branched C1 to C4 alkyl radical and R2 is a saturated or unsaturated, linear or branched C1 to C8 hydrocarbon rest, essentially in the form of an isomer of cis-configuration, characterized in that a substrate of formula 
in which R1 and R2 have the meaning indicated above, is hydrogenated in the presence of a Ru catalyst as previously described and at a hydrogen pressure comprised between atmospheric pressure and 500 bar (5xc3x97107 Pa).
Another object of the invention is a process for the preparation of a compound of formula 
wherein the dotted lines and the symbols n, Z, R2, R6, R7 and R8 are defined as in formula (IV), essentially in the form of an isomer of cis-configuration, characterized in that a substrate of formula (IV) as defined above is hydrogenated in the presence of a ruthenium catalyst according to the invention and at a hydrogen pressure comprised between atmospheric pressure and 500 bar.
Preferred embodiments of these two processes resort to the use of catalysts which comprise appropriate chiral chelating diphosphines, such as to provide the compound of formula (I) or (VI) essentially in the form of an optically active isomer of cis-configuration.
As is current in the art, the substrate is preferably used in a pure state and free of oxygen.
The hydrogenation reaction can be carried out in a non-coordinating or weakly coordinating solvent, the latter being defined as already described above. Specific examples thus include dichloromethane, dichloroethane, ethyl pivalate, methyl acetate, ethyl acetate, isopropyl acetate, acetone, 2-butanone, 3-pentanone, hexane, heptane, cyclohexane, cycloheptane and methyl tert-butyl ether, and their mixtures. The use of a solvent comprising dichloromethane is preferred.
Alternatively, the hydrogenation medium in which the reaction takes place may consist essentially of the substrate, or be highly concentrated in the latter.
According to a preferred embodiment of the hydrogenation process of the invention, the catalyst is generated in situ before the hydrogenation of the substrate, or in the presence of a small amount of the latter.
All the racemic or achiral ligands previously cited can be used to generate catalysts which make it possible to prepare the compounds of formula (I) or (VI) essentially in the form of the cis-configuration isomer, whereas the optically active chelating diphosphines provide the desired optically active cis form of the cited compounds of formula (I) or (VI).
Of course, racemic ligands can be subjected to separation, for example by means of chiral columns, to provide the corresponding enantiomers.
Following a particularly preferred embodiment of the hydrogenation process according to the present invention, methyl 3-oxo-2-pentyl-1-cyclopentene-1-acetate is used as the substrate, in order to obtain Hedione(copyright) in the form of the preferred cis- and (+)-cis-configuration isomers.
The catalysts according to the present invention which start from the [(COD)Ru(2-methylallyl)2] precursor and have ligands of the DuPHOS type, and in particular Me-DuPHOS, have proved to be particularly useful for the hydrogenation of this substrate, carried out in a solvent of dichloromethane.
Other preferred conditions for the hydrogenation of this substrate include the use of a catalyst comprising [(COD)Ru(2-methylallyl)2] and (R)-(S)-JOSIPHOS as the ligand, in a hydrogenation medium comprising a hydrocarbon such as hexane, heptane or their saturated cyclic analogues, and more preferably methyl tert-butyl ether.
This latter preferred embodiment of the hydrogenation process of the invention makes it possible to obtain (+)-cis-Hedione(copyright) with an enantiomeric excess of 80% or more. Still another preferred embodiment resorts to the use of [Ru(COD)(COT)] and (R)-(S)-JOSIPHOS.
The hydrogenation can be carried out at pressures from about atmospheric pressure to 500 bar (5xc3x97107 Pa). Pressure values comprised between 20, and more preferably 50 to 200 bar or even higher are quite convenient.
The reaction may take place at temperatures of up to 50 to 60xc2x0 C., or even 100xc2x0 C. Preferably, one will work at room temperature or even a lower temperature. It has been found for example that temperatures down to xe2x88x9210xc2x0 C., or even lower, made it possible to obtain good results.
The molar concentrations in which these catalysts may be typically used can go up to 4 molar %, relative to the substrate, but preferred embodiments of the hydrogenation process of the invention comprise using the catalyst in a molar concentration of about 0.01 to 1%, more preferably between 0.01 and 0.5 molar %. Excellent results could be systematically obtained with concentrations of 0.02 to 0.1%, more particularly 0.025 to 0.05 molar %, relative to the substrate.
Moreover, it has also been found that it is advisable to use solutions in which the substrate is concentrated, and the best results have been obtained when the concentration of the substrate in the hydrogenation medium was from about 0.4 to 1.5 molar with respect to the volume of this medium.
To hydrogenate the reaction mixture, the latter is pressurized under hydrogen in a conventional manner and as is described in the examples below. With the catalysts of the invention, used in concentrations of the order of 0.05 molar % relative to the substrate complete conversion of the latter could be obtained in less than 24 h, and in the best cases in 6 hours or less.
The invention will now be described in greater detail by way of the following examples, wherein the temperatures are indicated in degrees Celsius and the abbreviations have the usual meaning in the art.
These examples illustrate particular and best embodiments of the invention, many variations of which can be readily construed from the description above. Namely, in the many examples of catalysts taught in the WO 97/18894 application, which resulted from the various combinations of the preparation parameters also described in detail in the preceding pages of the instant disclosure, the use of about 1 molar equivalent of acid comprising a non-coordinating anion per mole of Ru(II) complex, as instantly taught, provided enhanced novel catalysts. The contents of this WO 97/18894 application is therefore hereby included by reference, to the extent that it provides specific examples of the many catalysts that can be obtained by varying the nature of the Ru(II) complex precursor, of the diphosphine ligand, of the non-coordinating anions and their precursors, and of the non-coordinating or weakly-coordinating solvent.
It is to be appreciated that the use of the respective enantiomers of the ligands mentioned throughout this specification, for example of (S,S)-(+)-MeDuPHOS or (S)-(R)-JOSIPHOS, makes it possible to obtain the corresponding enantiomers of compounds of formula (I) and (VI) mentioned above.
In the examples hereafter, reference to a xe2x80x9cgloveboxxe2x80x9d means a glovebox under Ar or nitrogen and the oxygen content of which is under 10 ppm.